Substituted piperidine or pyrrolidine compounds for treating sigma-receptor modulated disorders

ABSTRACT

The invention concerns the use of compounds of formula (I), in which R 1 , R 2 , R 3 , R 4 , R 5 , m and n have the meanings indicated herein for use in the treatment of sigma-receptor modulated disorders. ##STR1##

FIELD OF APPLICATION OF THE INVENTION

The invention relates to the novel use of known active compounds in thetreatment of illnesses which are favorably affected by substances havingaffinity for sigma receptors.

KNOWN TECHNICAL BACKGROUND

British Patent 1313781 describes substituted piperidines which aredistinguished by a long-lasting, centrally stimulating action. One ofthe active compounds coming under the British patent, for which the INNbudipine was later recommended, is being tested in the therapy ofParkinsonism. Furthermore, the prior art (e.g. German PatentSpecification 10 05 067, German Patent Specification 871 899, GermanPatent Specification 875 660, East German Patent Specification 50 603and U.S. Pat. No. 2,411,664) discloses a number of 1-pyrrolidino- and1-piperidinopropanols and -butanols, such as, for example, biperidin,cycrimine, pridinol, procyclidine, trihexyphenidyl, triperidin ordifenidol, which in some cases can likewise be employed in the therapyof Parkinsonism.

DESCRIPTION OF THE INVENTION

Surprisingly, it has now been found that the compounds described belowin greater detail have a high affinity for sigma receptors and aretherefore advantageously suitable for the treatment of illnesses whichcan be favorably affected by alterations in the function of sigmareceptors.

The invention relates to the use of compounds of the formula I ##STR2##in which either

R1 is phenyl,

R2 is phenyl,

R3 is hydrogen or 1-4C-alkyl,

R4 is hydrogen or 1-4C-alkyl,

R5 is hydrogen or 1-4C-alkyl,

m is the number 2

and

n is the number 0,

or in which

R1 is hydrogen,

R2 is hydrogen,

R3 is phenyl,

R4 is cyclopentyl, cyclohexyl, phenyl, 2-norbornen-5-yl ortricyclo[2.2.1.0²,6 ]hept-2-yl,

R5 is hydroxyl

m is the number 1 or 2

and

n is the number 2 or 3,

and their salts for the production of medicaments for the treatment ofsigma receptor-modulated illnesses.

1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and, inparticular, the methyl radical.

Suitable salts of compounds of the formula I are preferably allpharmacologically tolerable acid addition salts with the inorganic andorganic acids customarily used in pharmacy. Those which are suitable arewater-soluble and water-insoluble acid addition salts with acids suchas, for example, hydrochloric acid, hydrobromic acid, phosphoric acid,nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid,benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid,sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid,succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid,toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoicacid, it being possible to employ the acids in salt preparation -depending on whether it is a mono- or polybasic acid and depending onwhich salt is desired--in an equimolar quantitative ratio or onediffering therefrom.

Depending on the nature of the substituents, the compounds of theformula I can be optically active compounds. The invention thereforeincludes both the enantiomers and their mixtures and racemates.

Illnesses which may be mentioned which are favorably affected bysubstances having affinity for sigma receptors are psychoses(schizophrenia), hallucinations in combination with psychotic disordersand chronic psychological depressions, psychoneuroses, brain functiondisorders (cerebral ischemia, cognitive dysfunction), disorders ofintestinal function (absorption, secretion, motility) and of othersmooth muscular organs, such as vas deferens and bladder (urinaryincontinence), and other disorders such as are connected with affinitiesfor sigma receptors and such as are described, for example, in theliterature surveys of B. L. Largent et al. (Eur. J. Pharmacol., 155,345-7, 1988), S. I. Deutsch et al. (Clinical Neuropharmacology, 11(2),105-119, 1988), T. P. Su (Eur. J. Biochem., 200, 633-642, 1991) and J.M. Walker et al. (Pharmacol. Rev. 42, 355-402, 1990).

In the use according to the invention of the compounds of the formula Ifor the production of the abovementioned medicaments, thepharmacologically active compounds of the formula I and/or their salts(=active compounds) are processed with suitable pharmaceuticalauxiliaries or excipients to give tablets, coated tablets, capsules,suppositories, patches (e.g. as TTS), emulsions, suspensions orsolutions, the active compound content advantageously being between 0.1and 95% and it being possible to achieve a pharmaceutical administrationform (e.g. a delayed release form or an enteric form) exactly matched tothe active compound and/or to the desired onset of action by theappropriate choice of the auxiliaries and excipients.

The person skilled in the art is familiar on the basis of his expertknowledge with the auxiliaries or excipients which are suitable for thedesired pharmaceutical formulations. Apart from solvents, gel-formingagents, suppository bases, tablet auxiliaries and other excipients, itis possible to use, for example, antioxidants, dispersants, emulsifiers,antifoams, flavor corrigents, preservatives, solubilizers, colorants orin particular permeation promoters and complexing agents (e.g.cyclodextrins).

The active compounds can be administered orally, rectally, parenterallyor percutaneously.

In general, it has proven advantageous in human medicine to administerthe active compound(s) in the case of oral administration in a dailydose from approximately 0.01 to approximately 20, preferably 0.05 to 5,in particular 0.2 to 2.0, mg/kg of body weight, if appropriate in theform of several, preferably 1 to 4, individual doses to achieve thedesired result. In a parenteral treatment, it is possible to use similaror (in particular in the intravenous administration of the activecompounds) generally lower doses. Any person skilled in the art caneasily determine the optimum dose necessary in each case and manner ofadministration of the active compounds on the basis of his expertknowledge.

If the compounds of the formula I and/or salts are employed for thetreatment of sigma receptor-modulated illnesses, the pharmaceuticalpreparations can also contain one or more pharmacologically activeconstituents of other pharmaceutical groups.

The invention furthermore includes the use of the compounds according tothe invention for the treatment of sigma receptor-modulated illnesses.

One embodiment of the invention is the use of compounds of the formula Iin which

R1 is phenyl,

R2 is phenyl,

R3 is hydrogen or 1-4C-alkyl,

R4 is hydrogen or 1-4C-alkyl,

R5 is hydrogen or 1-4C-alkyl,

m is the number 2

and

n is the number 0.

A further embodiment of the invention is the use of compounds of theformula I in which

R1 is hydrogen,

R2 is hydrogen,

R3 is phenyl,

R4 is cyclopentyl, cyclohexyl, phenyl, 2-norbornen-5-yl ortricyclo[2.2.1.0²,6 ]hept-2-yl,

R5 is hydroxyl

m is the number 1 or 2

and

n is the number 2 or 3.

A further embodiment of the invention is the use of compounds of theformula I in which R1 is phenyl, R2 is phenyl, R3 is hydrogen, R4 ismethyl, R5 is methyl, m is the number 2 and n is the number 0, and theirsalts for the production of medicaments for the treatment of sigmareceptor-modulated illnesses.

A further embodiment of the invention is the use of compounds of theformula I in which R1 is phenyl, R2 is phenyl, R3 is methyl, R4 ismethyl, R5 is methyl, m is the number 2 and n is the number 0, and theirsalts for the production of medicaments for the treatment of sigmareceptor-modulated illnesses.

A further embodiment of the invention is the use of compounds of theformula I in which R1 is hydrogen, R2 is hydrogen, R3 is phenyl, R4 is2-norbornen-5-yl, R5 is hydroxyl, m is the number 2 and n is the number2, and their salts for the production of medicaments for the treatmentof sigma receptor-modulated illnesses.

A further embodiment of the invention is the use of compounds of theformula I in which R1 is hydrogen, R2 is hydrogen, R3 is phenyl, R4 iscyclopentyl, R5 is hydroxyl, m is the number 2 and n is the number 2,and their salts for the production of medicaments for the treatment ofsigma receptor-modulated illnesses.

A further embodiment of the invention is the use of compounds of theformula I in which R1 is hydrogen, R2 is hydrogen, R3 is phenyl, R4 isphenyl, R5 is hydroxyl, m is the number 2 and n is the number 2, andtheir salts for the production of medicaments for the treatment of sigmareceptor-modulated illnesses.

A further embodiment of the invention is the use of compounds of theformula I in which R1 is hydrogen, R2 is hydrogen, R3 is phenyl, R4 iscyclohexyl, R5 is hydroxyl, m is the number 1 and n is the number 2, andtheir salts for the production of medicaments for the treatment of sigmareceptor-modulated illnesses.

A further embodiment of the invention is the use of compounds of theformula I in which R1 is hydrogen, R2 is hydrogen, R3 is phenyl, R4 iscyclohexyl, R5 is hydroxyl, m is the number 2 and n is the number 2, andtheir salts for the production of medicaments for the treatment of sigmareceptor-modulated illnesses.

A further embodiment of the invention is the use of compounds of theformula I in which R1 is hydrogen, R2 is hydrogen, R3 is phenyl, R4 istricyclo[2.2.1.0²,6 ]hept-2-yl, R5 is hydroxyl, m is the number 2 and nis the number 2, and their salts for the production of medicaments forthe treatment of sigma receptor-modulated illnesses.

A further embodiment of the invention is the use of compounds of theformula I in which R1 is hydrogen, R2 is hydrogen, R3 is phenyl, R4 isphenyl, R5 is hydroxyl, m is the number 2 and n is the number 3, andtheir salts for the production of medicaments for the treatment of sigmareceptor-modulated illnesses.

The compounds of the formula I are known, for example from the patentspecifications mentioned in the prior art.

Pharmacology

The affinity and selectivity of the compounds described above in greaterdetail for sigma receptors in comparison with NMDA receptors weredetermined following published methods (Kornhuber et al.: Eur. J.Pharmacol. 162, 483-490, 1989 and Neurosci. Lett. 163, 129-131, 1993).The table shows the exemplary comparison of the compound budipine withaminoadamantane derivatives, which are also employed for the therapy ofParkinsonism. A higher affinity and selectivity (lower K_(i) value) ofbudipine for sigma receptors has now surprisingly been found.

    ______________________________________                                                     Sigma receptors                                                                               (pentazocine     NMDA receptors                    K.sub.i values (μM)     binding)      (MK 801 binding)                   ______________________________________                                        Budipine     2.0         11.7                                                   Amantadine                20.3              10.5                              Memantine                 20.0               0.5                            ______________________________________                                    

We claim:
 1. In a method for treating a sigma receptor-modulated illnesswhich comprising administering an effective amount of an active compoundto a subject in need of such treatment, the improvement wherein theactive compound is a compound of formula I ##STR3## in which R1 isphenyl,R2 is phenyl R3 is hydrogen or 1-4C-alkyl, R4 is hydrogen or1-4C-alkyl, R5 is hydrogen or 1-4C-alkyl, m is the number 2and n is thenumber 0,or a pharmacologically-acceptable salt thereof.
 2. A method asclaimed in claim 1 wherein the active compound is budipine and whereinthe illness is a psychosis.
 3. A method as claimed in claim 1 whereinthe compound is budipine and the illness is a brain function disorder.4. A method of claim 3 wherein the brain function disorder is cerebralischemia or cognitive dysfunction.
 5. A method as claimed in claim 1wherein the compound is budipine and the illness is an intestinalfunction disorder.
 6. A method of claim 5 wherein the intestinalfunction disorder is absorption, secretion or motility.
 7. A method asclaimed in claim 1 wherein the compound is budipine and the illness isan urogenital tract disorder.
 8. A method of claim 7 wherein theurogenital tract disorder is urinary incontinence.